Methylbenz[a]anthracenes (MBAs) have been found in cigarette smoke condensate, stack gas and roofing tar extracts and are potentially environmental hazards to man. Among the twelve isomeric MBAs, 7-MBA is the most active skin carcinogen, 6-, 8-, 12-MBA are less active, and the other MBAs are either inactive or slightly active when injected subcutaneously or painted on the skin of rats and mice. The molecular basis for the carcinogenicity differences of the twelve MBAs is currently unknown. Since MBAs require metabolism to exert their carcinogenicity, the possible differences in their metabolic pathways which may account for their relative carcinogenic potencies will be investigated. It ha been proposed (incorrectly, we believe) that the methylsubstituents of the MBAs inhibit the metabolism at the methyl-substituted double bond. Thus we propose that, in spite of the methyl substituent, each MBA may be metabolized to the bay-region 3,4-dihydrodiol, 1,2-epoxides which are currently believed to be the ultimate carcinogens. The proposed research will be carried out in six stages: (i) snythesis of unlabeled and tritium-labeled MBAs by established and newly developed methods; (ii) detailed metabolism studies of each MBA in liver, lung, and skin microsomes and homogenates from untreated, phenobarbital- and 3-methylcholanthrene- pretreated rats and mice; and (iii) identification of metabolites derived enzymatically from each MBA and purified by high performance liquid chromatography by physicochemical methods such as ultraviolet and fluorescence spectrophotometry, mass spectrometry, nuclear magnetic resonance spectrometry, and spectropolarimetry; (iv) large-scale preparations of MBA metabolites by enzymic and/or ascorbic acid-ferrous sulfate-EDTA methods; (v) mutagenicity tests of MBA and metabolites with Salmonella typhimurium tester strain TA100 and with Chinese hamster V79 cells; and (vi) tumor-initiating activities of the MBAs and their metabolites on mouse skin. These studies will provide detailed understandings of the structure-activity relationship of the twelve MBAs and the molecular basis for their relative carcinogenic potencies based on their metabolic pathways.